Derivatives of the cyclopentanopolyhydrophenanthrene series and process of making same



"cholane-17-one-3-aldehydes,

Patented Feb. 2, 1943 DERIVATIVES OF THE CYCLOPENTANO-POLYHYDROPHENANTHRENE SERIES AND PROCESS OF MAKING SAME I Karl Miescher,Riehen, and Albert Wcttstein,

' Basel, Switzerland, assignors, by mesne assignments, to CibaPharmaceutical Products, Incr-. porated, Summit, N. .I.,'a corporationof New Jersey No Drawing. Application February \19, 1940, Serial No.319,806. In Switzerland July 12, 1937 7 Claims.

ample aldehydes derived from aetio-cholane, 1

pregnane, oestrane or hydro-oestrane and their stereo-isomers,homologues and partial dehydrogenation products. They may contain anyother desired substituents, for example substituted or unsubstitutedhydroxyl, carbinol, amino, carboxyl or hydrocarbon groups, or halogenatoms or ketogroups or their enol derivatives. Naturally suchsubstituents may also react in some cases with the aliphatic diazocompounds so that in addition to the reaction with the aldehyde groupthe introduction of further substituted or unsubstituted hydrocarbonresidues may take place. The parent materials may be saturated compoundsor they may contain one or more unsaturated linkages. Thus the processmay start for example from saturated and unsaturated3-oxy-aetio-allocholane-l'l-aldehydes,3-keto-aetio-allo-cholanel7-aldehydes or their enol derivatives, aetio-3-carboxy-aetiocholane-l'l-aldehydes,3-keto-ll-oxy-aetio-cholane-l'I-acetaldehydes, 3-oxy-, 3-ketoor3-halogen-bisnor-cholane-aldehydes, oxyor keto-norcholane-aldehydes or-cholane-aldehydes, and

difier from the foregoing aldehydes in the configuration at the carbonatoms 3, 5, 9, ll and/or17. I Among aliphatic diazo compounds there areincluded quite generally diazomethane and its.

monoand di-substitution products particularly with any desired radicalscontaining carbon, for

example monoand; di-alkyl-, cyclo-alkyln aralkylandaryl-diazo-compoundssuch as diazoethane, diazobutane, further diam-propylene,

phenyldiazo-methane, diazoketones such as diazo-acetone,diazo-acetophenone, diazo-benzoylacetone, furthermore salts ofdiazomethane-disulfonic acids, diazo-camphor, diazo-monoand-dicarboxylic acid derivatives, such as diazoacetic acid esters, amidesor nitriles or their substitution products, especially withalkylcycloalkyl-, aralkyland aryl radicals, diazomalonic acid-,diazosuccinic acid-, diazobenzoylmethane carboxylic acid-esters,-amides, -nitriles and the like. In the latter cases the saponificationof the substituted carboxyl groups and an elimination of the carboxylgroups may follow the reaction With the aldehyde group.

It may be left undecided whether in the course of the reactionintermediate products of the furodiazole type of little stability areformed. In any case there are obtained with elimination of nitrogenketones of the formula /H RCOOR1 in which R represents a radicalcontaining the ..cyclopentano-polyhydrophenanthrene ring structure andsubstituted as may be desired, R1 and R2 represent for example hydrogen,radicals contain- .ing carbon such as substituted and unsubstitutedhydrocarbon radicals, substituted carboxyl groups, sulfonic acid groupsor acyl groups.

reagents such as semicarbazide or trimethylammonium acetic acidhydrazide, Orby a combination-'otany of these methods. They arecompounds of therapeutic value or canbe converted into such compounds. 7

Ethylene oxide derivatives of the formula (in which R, R1 and R2 havethe meanings above indicated) may be formed as by-products. Thesecompounds are likewise valuable products since they can easily be splitaccording to known methods (see, for example Richter-Anschiitz,

Chemie der Kohlenstoffverbindungen, 12th edition, vol. I, page 403) toproduce for example glycols or derivatives thereof such ashalogenhydrins, a-amino-alcohols, glycol-mono-esters or ethers andglycol di-esters, or then alcohols, ketones, a-oxy-nitriles and thelike. They can be isolated by physical methods similar to thoseavailable for isolating the ketones and frequently advantageously fromthe non-ketonic fraction, or by chemical methods, for example aftersplitting the ethylene oxide bridge by esterification for example withchlorosulfonic acid or phthalic acid.

The following examples illustrate the invention, the parts being byweight:

Example 1 1 part of A -aetio-cholene-3-ol-17-a1dehyde (obtained byreducing A -21-acetoxy-pregnene- 3-,ol-20-one with aluminiumisopropylate, hydrolysing and splitting the glycolic group with periodicacid) is dissolved in ether and the solution is mixed with an etherealsolution of diazomethane prepared from 3 parts of nitrosomethylurethane.After the solution has been allowed to stand for several days thesolvent is evaporated and the residue is heated with a solution of thechloride of trimethylamino-acetic acid hydrazide in alcohol and aceticacid. The latter solution is poured into Water and the resulting acidsolution is at once neutralized with alkali solution and extracted withether. The ketone condensation product dissolved in the aqueous layer issaponified by cautious addition of sulfuric acid and after standing forsome time the solution is extracted with ether. The washed etherealsolution yields on evaporation A -pregnene-3-ol-20-one of the formulaCH3 CH3 H A OW.

Example 2 An ethereal solution of 3 parts of A-aetiocholene-3-one-17-aldehyde (obtainable by reducing A-21-acetoxy-pregnene-3-ol-20-one with aluminium isopropylate,hydrolysing, condensation of the glycolic group with acetone,dehydration of the 3-hydroxyl group by means of an aluminium alcoholatein the presence of a ketone, splitting 01f the acetone and treating thefree glycol with periodic acid) is mixed with an ethereal solution ofdiazomethane prepared from 5 parts of nitroso-methylurethane and thewhole is allowed to stand for several days. The ether is then evaporatedand the residue is sublimed at 115 C. in a high vacuum (0.0005millimetre). The sublimate is recrystallized from hexane or from ethylacetate whereby there is obtained M-pregnene-3z20-dione- (progesterone)of the formula a Ca It crystallizes in dimorphous forms meltingrespectively at C. and 129 C.

If an enol derivative, for example an enol ester or enol ether of the3-keto-17-aldehyde is used instead of the 3-keto-l7-aldehyde itselfthere is obtained the corresponding 3-enol derivative of progesterone.

Example 3 300 mgr. of A -aetio-cholene-3-one-1'7-aldehyde is dissolvedin 30 c. c. of ether, and a solution of 200 mgr. of diazomalonic acidethyl ester in 20 c. c. of ether is added. When the reaction iscomplete, the solution is washed with water and soda solution and isthen evaporated to dryness in vacuo. The residue is hydrolyzed byboiling with 10 c. c. of methyl alcoholic potassium hydroxide solutionof 5 per cent strength for 2 hours under reflux. To the solution, whichnow contains the potassium salt, 8 c. c. of sulfuric acid of 2N strengthare added, and the whole is boiled under reflux for a further 2 hours.It is now poured into water, extracted with ether, and the etherealsolution, after washing and drying, is evaporated. The resultingyellowish crystalline mass is sublimed in a high vacuum at 120 C. andthe sublimate is recrystallized from hexane, whereby the progesteronedescribed in Example 2 is obtained.

Instead of diazomalonic ester, a diazoacetic ester may also be used.

If A -aetio-cholene-3-ole-l7-aldehyde is used in place of A-aetio-cholene-3-one-l'I-aldehyde as parent substance, the A-pregnenole-(3)- one-(20) described in Example 1 is obtained.

Example 4 To 200 mgr. of A -aetio-cholene-3-ol-l'l-aldehyde, dissolvedin 20 c. c. ether there are added mgr. of Z-diazo-propane in 15 c. c.ether. After standing for several days, the ethereal solution is washedwith water and sodium carbonate solution, dried and evaporated. Theresidue is purified in known manner by chromatographic analysis and theA -21-dimethy1- pregnene-3-ol-20-one of theformula Example 5 500 mgr, ofA aetio-cholene3-ple-l7-aldehyde are dissolved in 50 ,c. c of absoluteether and a solution of 250 mgr. of diazoethane in 30 c. c. of ether isadded. When the reaction is complete, the reaction solution is washedwith water, sodium carbonate solution and again with water, after whichit is dried and evaporated in vacuo. The residue is sublimed at 140/0.01mm. and recrystallized from dilute acetone, when the A-21-methyl-pregnene-3-ole-20-one is obtained in the form of colourlessneedles of M. P. 170-171 C. It has the formula CH3 C H:

A 'C O OHzCHs CH3 CH3 -o 0 onion;

Ill

,J l is obtained with diazoethane in a fully analogous manner. Byperoral administration in the corpus-luteum test it proves to be active,in contrast to progesterone,

By starting from aldehydes of the pregnane series for example the A"-pregnadiene-lione-21-a1, there are obtained analogously thecorresponding 21-ketones.

What we claim is:

1. A process for the manufacture of derivatives of thecyclopentano-polyhydrophenanthrene series, comprising causing analdehyde of this series to react with an aliphatic diazo compound.

2. A process for the manufacture of derivatives of thecyclopentano-polyhydrophenanthrene series, comprising causing analdehyde of this series to react with an aliphatic diazo compound andtreating the reaction product so as to split the ethylene oxide compoundformed.

3. A process for the manufacture of derivatives of thecyclopentano-polyhydrophenanthrene series, comprising causing analdehyde of this series to react with aliphatic diazo-carboxylic acidderivatives. selected from the group consisting of diazo-acetic acidesters, diazoacetic acid amides, diazo-acetic acid nitriles and theiralky1-, cycloalkyl-, aralkyland aryl-substituted products, diazomalonicacid esters, diazomalonic acid amides and diazomalonic acid nitriles.

4. A process for the manufacture of derivatives of thecyclopentano-po1yhydrophenanthrene series, comprising causing analdehyde of this series to react with aliphatic diazo-carboxylic acidderivatives selected from the group consisting of diazo-acetic acidesters, diazo-acetic acid amides, diazo-acetic acid nitriles and theiralkyl-, cyc1oalky1-, aralkyland aryl-substituted products, diazomalonicacid esters, diazomalonic acid amides and diazomalonic acid nitriles andhydrolyzing and decarboxylating the reaction product.

5. The compounds of the cyclopentano-polyhydrophenanthrene seriescontaining at the 17- position of the nucleus the grouping in which R1and R2 each represents alkyl.

6. The compounds of the cyclopentano-polyhydrophenanthrene seriescontaining at the 1'7- position of the nucleus the grouping CH: -co-o 7.The compound of the formula on; CH3 CH3 1-00-0 OH: Y

KARL MIESCHER. ALBERT WETTSTEIN.

